The present invention is the continuation application of “A specific indoles compounds and preparation methods thereof” (Application Number: 02138518.1; granted on May 4, 2005), “A pharmaceutical emulsion suitable for undissolved medicaments and preparation methods thereof” (Application Number: 200410052816.5; Application date: Jul. 14, 2007), “Preparation methods of N(1)-hydrocarbyl-3′-oximido indirubin derivatives (1) and medical uses thereof” (Application Number: 200510094482.2; granted on: Aug. 1, 2007) and “A dispersing agent suitable for undissolved medicaments” (Application Number: 200610038112.1; Application date: Jan. 17, 2006).
Monomeric compounds from plants are the major class among anti-tumor drugs. For instance, camptothecin isolated from Camptothera acuminate and paclitaxel obtained from Cephalolaxus are the well-known examples.
Through researching traditional medicinal plants with modern pharmaceutical methods, it is found that indirubin (1, indirubin, 2′,3-bisindole, purple), a bisindole derivative contained in Qingdai, is effective in the treatment of chronic myelocytic leukemia (CML). It has advantages of quick onset, low dose, little side effects, and low cost, etc. Subsequently, extensive structural modifications and biological activity studies on bisindole compounds obtained from Qingdai [including indigo (2), 2,2′-bisindole, blue; isoindigo (3), 3,3′-bisindole, brown] were carried out. As a result, N-1-methylisoindigo was found to have better efficacy and lower toxicity than indirubin.

Further studies demonstrate that the pharmacodynamic mechanism of indirubin and derivatives thereof inhibit tumor proliferation by inhibiting cyclin-dependent kinases (CDKs)
The cyclin-dependent kinases (CDKs) are typical serine (Ser)/threonine (Thr) kinases and signaling molecules of cell growth. CDKs mainly act on different phases of the cell cycle (a cell cycle is classified into four phases: G1, S, G2 and M), and allow for cell growth, proliferation (DNA replication and chromosome segregation), dormancy (cells are out of cell cycle and enter the quiescent period of cell division, known as the G0 phase) or apoptosis. CDKs can also regulate nerve and thymus function. Unlike other kinases, a hybrid dimer complex formed with the corresponding cyclins is necessary for the catalytic functions of CDKs. At least 9 CDKs (CDK 1˜9) and 11 cyclins (A˜J) have been identified in human cells. Different CDKs bind to different cyclins or cyclin subunits. For instance, CDK1 (cdc2) binds to cyclin A and B1-B3; CDK2 binds to cyclin A, D1-D3 and E; CDK4, CDK5 and CDK6 bind to cyclin D1-D3; CDK5 also binds to pk35; CDK7 binds to cyclin H; and CDK6 binds to cyclin K which is D-related.
According to biomedicine research that have won 2001 Nobel Prize, “the relationship between proliferation and cancer”, all kinds of abnormality of CDKs are present in almost all tumor cells[1-2], and cancer cells enter S, G2 and M phases in cycles and immortalize. For example, over 85% of breast cancer patients demonstrate abnormality in cyclinE/CDK4/6[3]. Multiple tumors can be treated by inhibiting CDKs to effectively preventing cell proliferation (but not killing cells), thus, either promoting cell differentiation, or promoting cell apoptosis. It is believed that CDK inhibitors are a new class of anticancer drugs with broad spectrum. In addition, these drugs will have strong selectivity, good efficacy and low toxicity due to their cytostatic, not cytotoxic activity.
It is shown that CDK inhibitors effectively inhibit growth of various cancer cells, such as cancer of breast, colon, prostate, and brain tumor, etc. These compounds can also effectively inhibit clinically refractory androgen-independent prostate cancer cells (PC-3, DU-145), hormones and many other chemotherapy-resistant advanced metastatic prostate cancer cells due to their ability to inhibit cell proliferation, which is more significantly. As a result, it has become a new reasonable strategy to develop anticancer drugs by looking for CDK inhibitors[4-6].
So far, nearly 10 types of small molecule CDK inhibitors and/or regulating agents have been studied, which are mainly ATP-regional oriented CDK inhibitors[7]. Indirubin and N-1-methylisoindigo, which have been used clinically are one type of CDK inhibitors. In addition, UCN-01 and flavopiridol, which was developed by the National Cancer Institute (NCI) of United States, have entered clinical trails[10].

In summary, indirubin bisindole derivatives are important CDK inhibitors that have little toxic side-effects. However, clinical applications of these compounds are influenced by their poor water-solubility and liposolubility. In recent years, extensive structural modifications for indirubin derivatives have been made by many foreign pharmaceutical research institutions and pharmaceutical companies. However, the anti-tumor effects of indirubin bisindole derivatives are still dissatisfactory.
In a word, there's an urgent need to develop new CDK inhibitors with excellent performance.